{
  "abstract": "Pulmonary arterial hypertension (PAH) is a severe and progressive disease characterised by excessive remodelling and proliferation within the pulmonary arteries, leading to an increase in mean pulmonary arterial pressure, ≥ 20 mmHg: there is no cure for the PAH.1 The second messenger cyclic AMP (cAMP) is reduced in PAH-pulmonary artery smooth muscle (PASMC). The prostacyclin receptor (IPR), a Gαs-coupled G protein-coupled receptor (GPCR), is a therapeutic target for PAH by increasing cAMP. Phosphodiesterase 1C (PDE1C), by hydrolysing cAMP, plays a crucial role in shaping cAMP gradients in in PASMC and accounts for increased IPR degradation and reduced response to IPR-agonist: IPR-PDE1C signalosomes ultimately promote disease progression.2 We aimed to define the functional role and interacting proteins of the IPR-PDE1C signalosome to underpin its role in PAH and how it could be targeted in the disease. Our data showed that decreased IPR function associated with PDE1C can be restored by 72h treatment of a PDE1 inhibitor, validating the role of the signalosome. By qPCR and mass spectrometry, we identified scaffolding proteins – DLG4 and Cavin1 – and E3 ubiquitin ligases – UBR5, SMURF2, NEDD42, Cullins1, -3, -4A, -4B and 7 – which may be crucial in the formation and regulation of the IPR-PDE1C signalosome. We believe disrupting the IPR-PDE1C signalosome by PDE1 inhibitors or peptide protein disruptors could prevent disease progression and improve PAH patient response to IPR-agonists.References Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R. Haemodynamic definitions and updated clinical classification of pulmonary hypertension, The European Respiratory Journal 2019;53(1):1801913. Murray F, Patel HH, Suda RYS, Zhang S, Thistlethwaite PA, Yuan JX-J, Insel PA. Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1. American Journal of Physiology- Lung Cellular and Molecular Physiology 2007;292(1), American Physiological Society, pp. L294–L303.",
  "authors": [
    {
      "affiliations": [
        "University of Aberdeen"
      ],
      "name": "Louise Cope"
    },
    {
      "affiliations": [
        "University of Aberdeen"
      ],
      "name": "Zaher Al Bakour"
    },
    {
      "affiliations": [
        "University of Aberdeen"
      ],
      "name": "James Hislop"
    },
    {
      "affiliations": [
        "University of Aberdeen"
      ],
      "name": "Fiona Murray"
    }
  ],
  "title": "P6  IPR-PDE1C in pulmonary hypertension: uncovering the signalosome",
  "uid": "7da31278-ab64-53e2-ab34-b40dc0904517"
}